Conditions which cause pain are obviously very prevalent in medicine. Very often, the cause of the pain is apparent. However, frequently, the physiological cause of the pain is not known. It is, of course, important to the clinician to determine the cause of the pain, so that proper treatment can be instituted. Prime examples of painful conditions wherein it is difficult to determine the cause of the pain are in patients experiencing spinal pain (i.e, lumbar, thoracic and cervical), particularly lower back ache or neck pain, and more particularly chronic cases. It is crucial in these conditions to determine whether they are caused by muscle or fibrous tissue injury, or are actually a result of nerve damage. The proper determination of the etiology will guide the clinician in the proper form of treatment.
Eighty-five percent of the United States population, at one time or another, seek medical consultation for back ache, particularly chronic back ache. Over 40 million people claim disability due to chronic back pain (or low back syndrome) and the medical costs alone to care for this group is over 40 billion dollars [Aronoff, G. M., Evaluation and Treatment of Chronic Pain, Urban and Schwarzenberg, Baltimore (1985)]. This does not include the enormous socio-economic loss, estimated to be in the trillions of dollars. In 1985, 2.7 million individuals received social security disability insurance at a overall cost of $ 18.9 billion [Social Security Administration, Report of the Commission on Evaluation of Pain, Washington D.C., Department of Health and Human Services (1986)].
Clinically, chronic pain, as opposed to acute pain, is continuous pain which persists for six months or more. Pain has been defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [International Association for the Study of Pain, chaired by Mersky (1979)]. Vasudevan has noted that there are several aspects to pain: nociception (the perception of pain, a physical stimulus); interpretation of the stimuli as "painful"; and the evaluation of the pain as creating suffering. [Vasudevan et al., "Counseling the Patient with Chronic Pain-The Role of the Physician", In Persistent Pain, Kluwer Academic Publishers, Boston (1988)].
In the present state of the art, there is no objective, accurate test for spinal pain, particularly chronic lower back (or lumbar) pain (hereinafter referred to as "CLP" which stands for "chronic lumbar pain") and/or radiating pain, and chronic cervical (neck) pain (hereinafter referred to as "CCP" which stands for "chronic cervical pain"). More specifically, there is no protein-based clinical test which quantitatively detects the presence or absence of CLP or CCP, much less one having the capability to quantitate or monitor the progression or regression of CLP or CCP. The existence of such a test would be of infinite value to the patient, the doctor, and the society which bears the cost-burden of this problem (i.e., insurance companies and government health and social security departments). An objective test for CCP or CLP would allow for the following:
1. Verify the presence or absence of the syndromes of CCP or CLP based on an organic cause. Ideally, this test would be performed on the first visit so that a baseline could be established to take advantage of the quantitative aspects of the test. If no organic cause existed, according to the test, then it would not be necessary to proceed with the more costly examinations (e.g., MRI's, CT scans, myelograms, discograms, bone scans, electromyelograms, and consultations) which are, in the present state of the art, required to rule out causes for this syndrome. If an organic cause is determined to exist, then the routine work-up could proceed with high expectations for success. At this point, if the routine tests for CLP or CCP are negative and the protein-based analysis disclosed herein is positive for back syndrome, then the treating physician would be justified in continuing to seek a correctable, organic cause. PA1 2. Monitor the progress and effectiveness of treatment. All chronic back or cervical syndromes are treated conservatively, initially. The effect of this treatment could be assayed and one or more of the following judgments could be made: continue with an improving test; discontinue with a worsening test; change treatment with a worsening test; recommend initial or revision surgery only when the test was worsening or not showing any improvement. Thus, an objective, biochemical test would increase the efficiency of conservative patient management and eliminate any unnecessary surgery. It is foreseeable that the test disclosed herein would become the standard for assessment, wherein surgery would be indicated only if the protein analysis indicated it. PA1 3. Identify the point of maximal medical improvement. By periodically administering the test during a course of treatment, the quantitative characteristic of the test would allow the physician to assess the degree of the symptoms of peripheral nerve damage of backache and/or radiating pain (particularly radiculopathy, which is currently thought to be due to nerve root damage) (CLP) and CCP and assist him in identifying the point where medical treatment should cease. At this point, treatment and rehabilitation efforts can stop and the physician, patient, and employer can feel comfortable with a recommendation to return to full-time work, limited work, settle claims, retirement, etc. Medical costs should be reduced while the efficacy of medical treatment improves. PA1 4. Identify those patients who are suffering disability from the pain of CLP or CCP from those who are not suffering from the pain of neck pain, backache and/or radiating pain. (Radiating pain is defined as pain that is perceived in one or both buttocks and/or one or both lower extremities. Radiating pain is currently divided into two categories: (1) referred pain which means pain that radiates into the buttock(s) and thighs and remains above the knee; and (2) radiculopathy which means pain which radiates into the buttock(s), thigh and below the knee, sometimes to the foot. Referred pain may be due to muscles, fascia, etc., while radiculopathy is thought to be due to nerve root damage.) This will assist the proper authorities in placing those who qualify for financial assistance because of an objectively documented back pain condition in the appropriate social program, and to identify and remove those who do not medically qualify. PA1 5. Aid the courts and others concerned with assessing correctly the compensable damages of pain and suffering secondary to neck pain, backache and/or radiating pain.
An objective test for peripheral nerve damage, in general, would allow the clinician to verify whether patients with peripheral nerve problems with neurological symptoms (for example: carpal-tunnel syndrome; brachial plexus problems; thoracic outlet syndrome; peripheral nerve injuries; peripheral nerve damage as a result of disease, ageing, congenital abnormalities, neoplasms; optic or auditory nerve damage due to many conditions, etc.) suffer from nerve damage, which would dictate a particular course of therapy.
Clinical tests for CCP or CLP include inspection, palpitation and manipulation. The vast majority of clinical tests depends upon the patient reporting a painful or other type of response, and are therefore unreliably subjective. Objective clinical tests in the current state of the art include reflex changes, spasm and properly performed straight leg raising tests, and may or may not aid in the diagnosis of lower back syndrome. Moreover, they neither quantitate nor monitor the progression of lower back syndrome.
Thermograms, psychological interviews (e.g., McGill and MMPI tests), polygraphs and instrumentation tests may also be used to assist in the diagnosis of CLP and CCP. However, none of these is completely accurate because they are also subjective and depend on the patient reporting the type and degree of response sustained.
Laboratory tests such as X-rays, CT scans, MRI's, myelograms, discograms, EMG's and bone scans can only delineate the presence or absence of possible pain-producing lesions which must then be correlated with the clinical findings of CLP or CCP. They do not detect the presence or absence of CLP or CCP per se, nor in any way quantitate them. Further, it is not uncommon to have false positive and false negative results with these tests (reported rates of error of about 20-50%). All or any of these tests may be negative and the patient may continue to complain; on the contrary, all or any of these tests may be positive and a patient may remain asymptomatic. Moreover, not only are these tests expensive, some of these tests expose the patient to unnecessary radiation.
The capacity to obtain diagnostic information from proteins, particularly blood proteins, has progressed rapidly since the middle of the 19th century when it was believed that serum contained but a single protein, albumin. By 1887, Lewith had demonstrated, by salt precipitation, that serum proteins could be separated into the albumins and globulins. The ratio of albumin to globulin (A/G ratio) was shown to have diagnostic value and is still in use today. With the introduction of electrophoretic separations, immuno-analytic techniques and enzymatic assays, the number of plasma proteins of diagnostic value has grown exponentially. The examination of specific blood proteins has proven to be an invaluable diagnostic aid, as in the monitoring of creatine phosphatase levels in determining cardiac damage following a myocardial infarct. The increased resolution and detection of plasma proteins with two-dimensional electrophoresis [O'Farrell, J. Biol. Chem., Vol. 250, pp. 4007-4021 (1975)] combined with silver-staining [Merril, Proc. Natl. Acad. Sci., USA, vol. 76, pp. 4335-4339(1979)] allows investigators an examination of over one thousand proteins in human plasma and approximately 300 proteins in human cerebrospinal fluid.
Anderson et al. [Proc. Natl. Acad. Sci., USA, Vol. 74, pp. 5421-5425 (1977)] initiated the mapping and the identification of the plasma proteins resolved by two-dimensional electrophoresis. The goal of this work was to use these proteins for screening genetic variants. By 1984, they were able to identify only 38 of 646 serumproteins visualized by their electrophoretic and staining systems [Anderson et al., Plasma Proteins, Vol. IV, pp. 221-269, Academic Press, New York (1984)].
It has been suggested that two-dimensional gel electrophoresis can be used to correlate the presence of a protein in serum or tissue, or an increase in its amount, with various diseases [Tracy et al., "Two-Dimensional Gel Electrophoresis: Methods and Potential Applications in the Clinical Laboratory", J. Clin. Lab. Autom.,Vol. 3, No. 4, p. 235 (1983)]. It has also been noted that development of a protein "profile" for disease states may be useful in diagnosis [Tracy et al., supra at 242].
However, the increase in resolution provided by two-dimensional electrophoretic techniques and the increased detection available with recently developed staining methods has not yet resulted in widespread clinical applications of this methodology. Thus, the diagnoses of disease states in general, and chronic back pain in particular, by way of two-dimensional gel analysis is new, there being only one such reported method. This method utilizes two-dimensional gel protein analysis of cerebrospinal fluid to distinguish Creutzfeldt-Jakob disease from other causes of dementia (Harrington et al., U.S. Pat. No. 4,892,814).
Harrington et al. [Clinical Chem., Vol. 31, pp. 722-726 (1985)] also found some proteins associated with Parkinson's disease and schizophrenia, which may or may not be of diagnostic value. Some proteins mapped and identified by two-dimensional electrophoresis of plasma [Anderson et al., 1984, supra] and cerebrospinal fluid [Goldman et al., Clin. Chem., Vol. 26, pp. 1317-1322 (1980)] have demonstrated to be polymorphic and thus may provide for genetic and forensic applications, but have not proven reliable as diagnostic markers for particular diseases.
To overcome the aforementioned deficiencies in the art, the present inventors have developed an objective, quantitative test for diagnosing peripheral nerve damage, particularly that which causes spinal pain and more-particularly CLP or CCP. The test utilizes two-dimensional electrophoresis to analyze the increased or decreased concentrations of certain proteins in a body fluid sample from a patient as compared to a normal control. During the course of developing this test, the present inventors discovered a protein marker, which is indicative of peripheral nerve damage.